[go: up one dir, main page]

WO2016165650A1 - Cocristal d'olaparib et d'urée et son procédé de préparation - Google Patents

Cocristal d'olaparib et d'urée et son procédé de préparation Download PDF

Info

Publication number
WO2016165650A1
WO2016165650A1 PCT/CN2016/079430 CN2016079430W WO2016165650A1 WO 2016165650 A1 WO2016165650 A1 WO 2016165650A1 CN 2016079430 W CN2016079430 W CN 2016079430W WO 2016165650 A1 WO2016165650 A1 WO 2016165650A1
Authority
WO
WIPO (PCT)
Prior art keywords
eutectic
crystal form
urea
ray powder
powder diffraction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/079430
Other languages
English (en)
Chinese (zh)
Inventor
陈敏华
张炎锋
刘凯
张晓宇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Crystal Pharmatech Co Ltd
Original Assignee
Crystal Pharmatech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Crystal Pharmatech Co Ltd filed Critical Crystal Pharmatech Co Ltd
Publication of WO2016165650A1 publication Critical patent/WO2016165650A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a eutectic of olaparib and urea, a preparation method and use thereof.
  • Olaparib was first developed by the British biotechnology company KuDOS Pharmaceuticals Co., Ltd. In 2005, after the acquisition of KuDOS, AstraZeneca continued to develop Olapani for the treatment of ovarian cancer. On December 19, 2014, Olapani was approved by the FDA in the United States. It is the first FDA-approved targeted drug for ovarian cancer patients with BRCA mutations. It is suitable for patients who have previously undergone chemotherapy. It has been shown in preclinical models that olaparib is the first oral poly ADP ribose polymerase (PARP) inhibitor that utilizes defects in the DNA repair pathway to preferentially kill cancer cells.
  • PARP poly ADP ribose polymerase
  • olapanib 4-[3-(4-cyclopropanecarbonyl-piperazine 1-carbonyl)-4-fluoro-benzyl]-2H-pyridazin-1-one, which has the structure of formula (I) Shown as follows:
  • KuDOS Korean Pharmaceutical Co., Ltd. discloses the free base form A of olaparib in patent CN101528714B, and the free base form L of olaparib is disclosed in CN101821242B.
  • the solubility of the free base crystal form listed in Olapani is low, and it is necessary to find a crystal form with high solubility to improve the absorption efficiency of the drug.
  • a eutectic is a crystal containing two molecules in the same crystal structure. The role between the two molecules is non- Covalent bonds (such as hydrogen bonds, ⁇ - ⁇ conjugates, halogen bonds, etc.).
  • the formation of drug eutectic does not destroy the covalent bond of the active ingredient of the drug, and has the opportunity to improve the crystallization and physicochemical properties of the drug itself, such as bioavailability (Pharmaceut. Res. 23 (8), 2006, pp. 1888-1897). .), Stability and Process Developability (Int. J. Pham. 320, 2006, pp. 114-123.), a new choice for pharmaceutical solid formulations.
  • the eutectic stability provided by the invention is good, and the wettability is low. Compared with the crystal form in the prior art, the solubility is improved, which is beneficial to improving the bioavailability of the drug, and is important for improving the efficacy and safety of the drug.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a eutectic of olrapani and urea with high solubility and good stability.
  • the eutectic of olrapani and urea provided by the present invention has the structural formula shown in formula (II).
  • the eutectic provided by the present invention is named as eutectic crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 17.4° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 10.5° ⁇ 0.2°.
  • the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having one or more of 2theta values of 21.1° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 12.2° ⁇ 0.2°. Characteristic peaks.
  • the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 21.1° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 12.2° ⁇ 0.2°.
  • the present invention provides a eutectic crystal form A having an X-ray powder diffraction pattern at a 2theta value.
  • a eutectic crystal form A having an X-ray powder diffraction pattern at a 2theta value.
  • 9.2° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 23.4° ⁇ 0.2° have characteristic peaks.
  • the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 9.2° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of eutectic crystal form A is substantially as shown in FIG. Further, a total of 26 diffraction peaks were shown in the X-ray powder diffraction pattern, and the positions and relative peak intensities of these diffraction peaks are shown in Table 1 or Table 2, in which the peak position was varied within a range of 0.2°.
  • a total of 34 diffraction peaks are shown in the X-ray powder diffraction pattern of the eutectic crystal form A.
  • the positions of the diffraction peaks and the relative peak intensities are shown in Table 3, wherein the peak position is 0.2. ° range changes.
  • the eutectic crystal form A shows an endothermic heat peak at 170 ⁇ 2 ° C in a spectrum measured by differential scanning calorimetry.
  • the eutectic crystal form A is shown by thermogravimetric analysis as being heated to 120 ⁇ 2 ° C with a weight loss gradient of about 1.8%.
  • the eutectic crystal form A can be obtained by reacting olaparib and urea in one or more solvent systems of alcohols, ketones, alkyl nitriles, and cyclic ethers.
  • the alcohol solvent is preferably ethanol
  • the ketone solvent is preferably acetone
  • the alkyl nitrile solvent is preferably acetonitrile or a cyclic ether solvent, preferably tetrahydrofuran or 1,4-dioxane.
  • Another object of the present invention is to provide a method for preparing eutectic of olrapani and urea, which comprises olaparib and urea in one of alcohols, ketones, alkylnitrile and cyclic ethers.
  • the reaction is carried out in a plurality of solvent systems, and is obtained by a crystallization method including, but not limited to, volatilization, stirring or cooling.
  • the alcohol solvent is preferably ethanol
  • the ketone solvent is preferably acetone
  • the mixed system containing olrapani, urea and solvent is subjected to multiple heating and constant temperature cooling operations, and solid precipitation, filtration, washing and drying are carried out to obtain the eutectic crystal of the present invention.
  • the solvent is ethanol or acetone or a combination of the two.
  • the olaparib free base is the original It is dissolved in the solvent, and urea is added to obtain the mixed system containing olaparib, urea and a solvent.
  • the heating constant temperature cooling operation refers to heating the system to a set higher temperature than room temperature, then thermostating for a set time, and finally cooling to a lower temperature set below room temperature.
  • the set higher temperature may be, for example, 40 to 80 ° C, preferably 50 to 70 ° C, more preferably 55 to 65 ° C, and a specific higher temperature value is about 60 ° C.
  • the set lower temperature may be, for example, -5 to 18 ° C, preferably -5 to 10 ° C, more preferably -5 to 5 ° C, and most preferably 0 to 5 ° C.
  • the rate of heating may be from 0.5 to 3 ° C/min, preferably from 1 to 2 ° C/min.
  • the rate of temperature drop may be from 0.1 to 1 ° C/min, preferably from 0.3 to 0.6 ° C/min.
  • the constant temperature period is preferably 5 hours or longer, more preferably 8 hours or longer, further preferably 9 hours or longer, more preferably 9 to 12 hours, specifically, for example, 10 hours.
  • the number of times of the heating constant temperature cooling operation is preferably 2 to 4 times, and most preferably 3 times.
  • the higher temperature is 40 to 80 ° C
  • the lower temperature is -5 to 18 ° C
  • the constant temperature is 5 hours or longer.
  • the higher temperature is 55 to 65 ° C
  • the lower temperature is 0 to 5 ° C
  • the constant temperature is 9 to 11 hours.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a co-crystal of olaparib and urea, and at least one pharmaceutically acceptable excipient, and a method of using the same for treating cancer.
  • a method of treating cancer includes administering to a cancer patient an effective amount of the pharmaceutical composition.
  • the cancer includes, but is not limited to, melanoma, pancreatic cancer, ovarian cancer, breast cancer, lymphoma, lung cancer, and the like.
  • the olapani and urea provided by the invention have good eutectic stability and low hygroscopicity, and no special drying conditions are needed in the preparation process, which simplifies the preparation and post-treatment process of the medicine, and is easy for industrial production. Moreover, the moisture content remains basically unchanged under different humidity conditions, which is convenient for long-term storage of medicines and has strong economic value.
  • the eutectic ratio of olaparib and urea provided by the present invention is free crystal form disclosed in patent CN101528714B
  • the higher solubility of A is beneficial to improve the absorption efficiency of the drug and improve the bioavailability of the drug, which is of great significance for improving the efficacy and safety of the drug.
  • Figure 1 is an XRPD pattern of eutectic crystal form A
  • Figure 3 is a TGA diagram of eutectic crystal form A
  • Figure 4 is a DVS diagram of eutectic crystal form A
  • Figure 5 is a DVS diagram of the free base crystal form A in the patent CN101528714B;
  • Figure 6 is a 1 H NMR chart of eutectic crystal form A.
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the powder of olaparib is obtained by a commercially available method.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • Preparation method of co-crystal of olaparib and urea 101.9 mg of olaparib free base dissolved in 3.0 mL of ethanol 98.7mg of urea was added, heated to 60 ° C at a heating rate of 1.0 ° C / min, stirred at 60 ° C for 600 min, then cooled to 5 ° C at a cooling rate of 0.37 ° C / min, repeating the above heating and cooling process three times, the reaction is over After filtration, the resulting solid was washed with ethanol and dried.
  • olaparib free base (amorphous) was dissolved in 0.6 mL of acetone, and 10.8 mg of urea was added to add After heating at a heating rate of 1.0 ° C / min to 60 ° C, stirring at 60 ° C for 600 min, cooling (cooling rate 0.37 ° C / min) to 5 ° C, repeat the above heating and cooling process three times, after the reaction is filtered, the resulting solid is washed with ethanol Dry, cool to room temperature and collect solids.
  • the solid obtained in this example was identical to the crystal form obtained in Example 1, and was a eutectic crystal form A, and its X-ray powder diffraction data is shown in Table 3.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the eutectic crystal form A prepared by the present invention and the free base crystal form A of CN101528714B were respectively prepared into a saturated solution by using SGF (simulated artificial gastric juice) of pH 1.8 and pH 6.5 FaSSIF (artificial intestinal juice under fasting state) for 1 hour. After 4 hours, the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 4.
  • the urea eutectic crystal form A of the present invention has higher solubility than the patent free base crystal form A after 4 hours; it is placed in FaSSIF for 4 hours.
  • the urea eutectic crystal form A of the present invention has a higher solubility.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un cocristal d'olaparib et d'urée et un procédé de préparation associé. L'invention concerne spécifiquement une forme cocristalline A et un diagramme de diffraction de rayons X sur poudre de cette forme cristalline présente des pics caractéristiques à des points où la valeur 2-thêta est de 17,4° ± 0,2°, 20,7° ± 0,2°, 10,5° ± 0,2°. Le cocristal selon l'invention présente une meilleure stabilité, une hygroscopicité inférieure et une solubilité plus élevée par rapport à des formes cristallines d'olaparib sans alcali.
PCT/CN2016/079430 2015-04-17 2016-04-15 Cocristal d'olaparib et d'urée et son procédé de préparation Ceased WO2016165650A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510185291 2015-04-17
CN201510185291.0 2015-04-17

Publications (1)

Publication Number Publication Date
WO2016165650A1 true WO2016165650A1 (fr) 2016-10-20

Family

ID=56333916

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/079430 Ceased WO2016165650A1 (fr) 2015-04-17 2016-04-15 Cocristal d'olaparib et d'urée et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN105753789B (fr)
WO (1) WO2016165650A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021220120A1 (fr) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Nouveaux composés utiles en tant qu'inhibiteurs de la poly(adp-ribose) polymérase (parp)
CN113636979A (zh) * 2021-08-12 2021-11-12 天津理工大学 一种奥拉帕尼与富马酸共晶晶型α及其制备方法与应用
WO2022058785A1 (fr) * 2020-09-16 2022-03-24 Nuformix Technologies Limited Co-cristaux d'acide oxalique olaparib et leur utilisation pharmaceutique
WO2022090938A1 (fr) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Dérivés de phtalazinone utiles en tant qu'inhibiteurs de parp
CN114539161A (zh) * 2020-11-11 2022-05-27 成都硕德药业有限公司 一种奥拉帕尼-尿素共晶及其制备方法
WO2022215034A1 (fr) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibiteurs de la poly(adp-ribose) polymérase
CN115197152A (zh) * 2022-07-11 2022-10-18 江苏海洋大学 一种奥拉帕尼药物共晶及其制备方法和应用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107286210B (zh) * 2017-06-19 2020-07-07 昆药集团股份有限公司 一种乙酰天麻素化合物及其制备方法、制剂与应用
CA3031777A1 (fr) 2018-01-31 2019-07-31 Apotex Inc. Forme cristalline d'olaparib
CN113121456B (zh) * 2020-01-15 2024-04-26 鲁南制药集团股份有限公司 一种阿昔莫司尿素共晶
CN111995582B (zh) * 2020-07-09 2021-12-03 天津理工大学 一种奥拉帕尼与尿素的共晶及其制备方法
CN111825621A (zh) * 2020-07-22 2020-10-27 天津理工大学 一种奥拉帕尼与丙二酸的共晶及其制备方法
CN111689905B (zh) * 2020-07-22 2021-12-03 天津理工大学 一种奥拉帕尼与马来酸的共晶及其制备方法
EP4429771A1 (fr) * 2021-11-10 2024-09-18 Nuformix Technologies Limited Co-cristaux d'acide hydroxybenzoïque d'olaparib et leur utilisation pharmaceutique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101528714A (zh) * 2006-10-17 2009-09-09 库多斯药物有限公司 4-[3-(4-环丙烷羰基-哌嗪-1-羰基)-4-氟-苄基]-2h-酞嗪-1-酮的多晶型物
CN101821242A (zh) * 2007-10-17 2010-09-01 库多斯药物有限公司 4-[3-(4-环丙烷羰基-哌嗪-1-羰基)-4-氟-苄基]-2h-酞嗪-1-酮

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0305681D0 (en) * 2003-03-12 2003-04-16 Kudos Pharm Ltd Phthalazinone derivatives
US20140235630A1 (en) * 2011-09-30 2014-08-21 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for the treatment of proliferative diseases
CN105254572A (zh) * 2015-11-09 2016-01-20 北京科莱博医药开发有限责任公司 一种奥拉帕尼的晶型及其制备方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101528714A (zh) * 2006-10-17 2009-09-09 库多斯药物有限公司 4-[3-(4-环丙烷羰基-哌嗪-1-羰基)-4-氟-苄基]-2h-酞嗪-1-酮的多晶型物
CN101821242A (zh) * 2007-10-17 2010-09-01 库多斯药物有限公司 4-[3-(4-环丙烷羰基-哌嗪-1-羰基)-4-氟-苄基]-2h-酞嗪-1-酮

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NARWAL, M. ET AL.: "Structural Basis of Selective Inhibition of Human Tankyrases", J.MED.CHEM., vol. 55, no. 3, 10 January 2012 (2012-01-10), pages 1360 - 1367, XP055166829 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021220120A1 (fr) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Nouveaux composés utiles en tant qu'inhibiteurs de la poly(adp-ribose) polymérase (parp)
CN116710424A (zh) * 2020-09-16 2023-09-05 努福米克斯技术有限公司 奥拉帕利草酸共晶体及其药学用途
US12012386B2 (en) 2020-09-16 2024-06-18 Nuformix Technologies Limited Olaparib oxalic acid cocrystals and their pharmaceutical use
WO2022058785A1 (fr) * 2020-09-16 2022-03-24 Nuformix Technologies Limited Co-cristaux d'acide oxalique olaparib et leur utilisation pharmaceutique
JP7453475B2 (ja) 2020-09-16 2024-03-19 ナフォーミックス テクノロジーズ リミテッド オラパリブシュウ酸共結晶及びその医薬的使用
JP2023538455A (ja) * 2020-09-16 2023-09-07 ナフォーミックス テクノロジーズ リミテッド オラパリブシュウ酸共結晶及びその医薬的使用
WO2022090938A1 (fr) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Dérivés de phtalazinone utiles en tant qu'inhibiteurs de parp
CN114539161A (zh) * 2020-11-11 2022-05-27 成都硕德药业有限公司 一种奥拉帕尼-尿素共晶及其制备方法
CN114539161B (zh) * 2020-11-11 2024-03-29 成都硕德药业有限公司 一种奥拉帕尼-尿素共晶及其制备方法
WO2022215034A1 (fr) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibiteurs de la poly(adp-ribose) polymérase
CN113636979A (zh) * 2021-08-12 2021-11-12 天津理工大学 一种奥拉帕尼与富马酸共晶晶型α及其制备方法与应用
CN115197152B (zh) * 2022-07-11 2023-07-14 江苏海洋大学 一种奥拉帕尼药物共晶及其制备方法和应用
CN115197152A (zh) * 2022-07-11 2022-10-18 江苏海洋大学 一种奥拉帕尼药物共晶及其制备方法和应用

Also Published As

Publication number Publication date
CN105753789B (zh) 2018-09-25
CN105753789A (zh) 2016-07-13

Similar Documents

Publication Publication Date Title
WO2016165650A1 (fr) Cocristal d'olaparib et d'urée et son procédé de préparation
CN113527203B (zh) 乐伐替尼甲磺酸盐的晶型及其制备方法和用途
RU2497820C2 (ru) Кристаллические формы и две сольватные формы солей молочной кислоты 4-амино-5-фтор-3-[5-(4-метилпиперазин-1-ил)-1 - н-бензимидазол-2-ил]хинолин-2(1н)она
CN101891738B (zh) 达沙替尼多晶型物及其制备方法和药用组合物
AU2016260279B2 (en) Crystals of azabicyclic compound
WO2016124137A1 (fr) Phosphate de l'inhibiteur du récepteur du facteur de croissance épidermique, forme cristalline du phosphate et procédé de préparation
WO2016091221A1 (fr) Sel de composé de pyrrolo[2,3-d]pyrimidine et nouveau polymorphe de sel
CN102086195A (zh) 达沙替尼多晶型物及其制备方法和药用组合物
AU2016239028B2 (en) P-toluenesulfonate for MEK kinase inhibitor, and crystal form thereof and preparation method therefor
CN105218484A (zh) 酒石酸卡利拉嗪及其制备方法和医药用途
CN105801476A (zh) 阿帕替尼甲磺酸盐ii晶型及其制备方法和应用
CN112010809A (zh) 奥拉帕尼的晶型i及其制备方法
WO2016127844A1 (fr) Forme cristalline de l'ipi-145 et son procédé de préparation
JP7252417B2 (ja) Ｒｈｏキナーゼ阻害剤としてのベンゾピラゾール化合物の塩形、結晶形及びその製造方法
WO2016101867A1 (fr) Forme alpha-cristalline de naproxen imatinib p-toluène sulfonate, procédé de préparation associé et composition pharmaceutique la contenant
CN104961681B (zh) 卡博替尼的粘酸盐及其晶型
CN110092789B (zh) 一种吲哚并[2,3-b]咔唑衍生物及其应用
CN118742553B (zh) 一种jak酪氨酸激酶抑制剂的多晶型物及制备方法
WO2012122921A1 (fr) Forme de sel d'un inhibiteur d'hydroxyphénylalanine kinase
WO2018214877A1 (fr) Forme cristalline de dézocine et procédé de préparation associé
WO2018137670A1 (fr) Forme cristalline du médicament inhibiteur de protéine virale (vx-287), et son procédé de préparation et d'utilisation
CN104059082B (zh) 硝基咪唑杂环类化合物及其在制备治疗结核病药物中的应用
ES2881960T3 (es) Inhibidores de proteina quinasa
CN111670191A (zh) 吡啶酮衍生物的晶型及制备方法和应用
WO2017152858A1 (fr) Forme cristalline de céritinib et procédé pour sa préparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16779625

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16779625

Country of ref document: EP

Kind code of ref document: A1